Background: Sickle cell anaemia (SCA) is characterized by chronic haemolysis, hypercoagulability and thrombosis, including stroke in 10% of children. The mainstays of treatment are hydroxyurea (HU) and chronic blood transfusion (BT). However, the biological mechanisms through which these therapies down-regulate thrombotic risk remain poorly understood.

Aims: We hypothesized that HU and BT may attenuate SCA-induced endothelial cell (EC) activation, coagulation activation and thereby mitigate thrombotic risk.

Methods: Following ethical approval and informed consent, 180 SCA children were recruited. Plasma samples were collected during steady-state and tested for a range of Weibel Palade body (WPB) markers, including VWF:Ag, VWF multimers, VWF propeptide (VWFpp), FVIII:C, Angiopoeitin-2 (Ang-2) and Osteoprotegerin (OPG). In addition, plasma ADAMTS-13 and thrombin generation were assessed.

Results: Plasma VWF:Ag, VWF:CB and VWFpp were all significantly reduced in the BT-treated children (n=84) compared to the HU-treated cohort (n=96) (Figure 1). In keeping with the concept of lower EC activation, plasma levels of other WPB biomarkers (Ang-2 and OPG) were also significantly decreased in the BT group (Figure 1). While ADAMTS13 activity did not differ between the cohorts, abnormal circulating VWF multimers were observed in the HU-treated but not in the BT children (Figure 1). The VWF/ADAMTS13 ratio was also significantly increased. Finally, markers of coagulation activation, including FVIII:C levels, endogenous thrombin potential (ETP) and peak thrombin were also significantly reduced in the BT cohort (Figure 1).

Conclusion(s): Although BT is recognised as the treatment of choice for children with severe SCA, the biological mechanisms underpinning its efficacy remain poorly understood. This is the first large study to directly address the effects of BT on SCA endotheliopathy and coagulopathy. Importantly, our novel data demonstrate that BT plays a critical role in maintaining normal EC quiescence and thus thrombin generation in SCA children.

Figure 1

Figure 1: Markers of Endotheliopathy and coagulation activation are reduced by chronic BT therapy Markers of acute and chronic EC activation comparing BT and HU, including: A- VWF:Ag, B- VWF:CB, C- VWFpp, D- Ang-2 and E- OPG. F- Percentage of high molecular weight -HMW- VWF multimers comparing BT, HU and control plasma. G- FVIII:C levels comparing BT and HU. Thrombin generation parameters comparing BT and HU, including H- Endogenous thrombin potential and I- Peak thrombin

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/blood-transfusion-maintains-endothelial-cell-quiescence-implications-in-the-prevention-of-stroke-in-paediatric-sickle-cell-anaemia/